U.S. Pat. Nos. 4,804,663 and 5,158,952 disclose a variety of 3-piperidinyl-1,2-benzisoxazole derivatives, processes for their preparation, pharmaceutical compositions comprising the derivatives, and methods of use thereof. These compounds have long-acting antipsychotic properties and are useful in the treatment of warm-blooded animals suffering from psychotic diseases. Among them, paliperidone, (±)-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6, 7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido [1,2-a]pyrimidin-4-one, is an antipsychotic agent and indicated for the both acute (short-term) and maintenance (long-term) treatment of schizophrenia. Paliperidone is represented by the following structural formula:

Processes for the preparation of paliperidone and related compounds are disclosed in U.S. Pat. Nos. 5,158,952, 5,254,556 and 5,688,799.
In the preparation of paliperidone, 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one of formula I:
is a key intermediate. According to U.S. Pat. Nos. 5,158,952 (hereinafter referred to as the '952 patent) and 5,254,556 (hereinafter referred to as the '556 patent), the compound of formula I can be prepared by the reaction of an optionally protected 2-aminopyridine compound with an α-acyl lactone compound in the presence of an activating reagent and in a suitable reaction-inert solvent such as toluene at a temperature 90° C. followed by treatment with ammonium hydroxide. The activating reagents include halogenating reagents such as, for example, phosphoryl chloride, phosphoryl bromide, phosphorous trichloride, thionyl chloride, and preferably phosphoryl chloride. The reaction mass is extracted with the solvents such as trichloromethane and then subjected to column chromatographic purifications.
The compound of formula I obtained by the process described in the '952 and the '556 patents is generally not of satisfactory purity. Unacceptable amounts of impurities are generally formed during the reaction between the 2-aminopyridine compound and the α-acyl lactone compound when the reaction is carried out in the presence of solvents like toluene, thus resulting in a poor product yield. In addition, the reaction proceeds at higher temperatures, and the process involves the additional step of column chromatographic purifications. Methods involving column chromatographic purifications are generally undesirable for large-scale operations, thereby making the process commercially unfeasible.
According to the U.S. Pat. No. 5,688,799 (hereinafter referred to as the '799 patent), the compound of formula I is prepared by the reaction of 2-amino-3-hydroxypyridine with 2-acetylbutyrolactone in the presence of p-toluenesulfonic acid in xylene solvent at reflux temperature for overnight using a water separator to yield 9-hydroxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one. The 9-hydroxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one is converted into its hydrochloride salt, followed by reaction with thionyl chloride in dimethylformamide to produce 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one.
The synthetic route for the compound of formula I as described in the '799 patent involves a lengthy process, the yields obtained in this process are very low, and also the process produces a product of unsatisfactory purity. This process is also commercially unfeasible. Moreover, the intermediate compound 9-hydroxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one obtained in this process is poorly soluble in xylene, resulting in deposit formation on the wall of the reaction vessel and discoloration of the reaction mixture to black. Furthermore, the reaction with thionyl chloride is characterized by a very severe smell, likely caused by reaction of residual 2-acetylbutyrolactone remaining from the previous step. The process generally results in a product of unreproducible yield and quality.
PCT Publication No. WO 2006/027370 describes a modified process for preparation of 9-hydroxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one involving the reaction of 2-amino-3-hydroxypyridine with 2-acetylbutyrolactone in the presence of p-toluenesulfonic acid and using chlorobenzene as a solvent at reflux temperature, i.e., at 125° C. The product is isolated by a process involving the addition of alcoholic solvent and filtration of the reaction mixture at 90-95° C.
The process described in WO 2006/027370 involves a lengthy process, the reaction proceeds at a high temperature i.e., above 125° C., it takes 19 hours for reaction completion, and also involves the hazard of filtration of a reaction mixture containing flammable solvents at 90-95° C. which poses problems in scale up operations. Based on the aforementioned drawbacks, this process may be unsuitable for preparation of the compound of formula I at laboratory scale and commercial scale operations.
A need remains for an improved and commercially viable process of preparing the compound of formula I or an acid addition salt thereof that will solve the problems associated with the processes described in the prior art, and that will be suitable for large-scale preparation. Desirable process properties include reduced reaction times, and greater simplicity, purity and yield of the product, thereby enabling the production of paliperidone and its pharmaceutically acceptable acid addition salts in high purity and in high yield.